Method for the production of solid formulations of sodium 3-hydroxy-3-methylbutyrate

ABSTRACT

Solid formulations of sodium 3-hydroxy-3-methylbutyrate are produced by the hydrolysis of 4,4-dimethyl-2-oxetanone with aqueous sodium hydroxide to give a solution of sodium 3-hydroxy-3-methylbutyrate and the solution obtained thus is absorbed onto synthetic silicic acid. Said formulations are lightly hygroscopic and easily handled.

[0001] The invention relates to a process for preparing solidformulations of the sodium salt of 3-hydroxy-3-methylbutyric acid(β-hydroxy-β-methylbutyric acid, HMB) of the formula

[0002] 3-Hydroxy-3-methylbutyric acid is an active compound which isused as a medicament and food additive for humans and animals, forexample for lowering blood cholesterol (WO-A-94/06417) or for decreasingnitrogen excretion, in particular in the case of ill and/or elderlyhumans (WO-A-94/14429). Customarily it is not the free acid which isused for this, but a physiologically acceptable salt, for example thecalcium salt. For economic reasons, in particular for applications inanimal nutrition or veterinary medicine, it would be desirable also tobe able to use the sodium salt. Although this has been mentionedrepeatedly in the literature, no industrial process for its preparationin solid form has been described and it has been found that it is notstorage-stable and is hygroscopic and is therefore difficult to process.

[0003] It is an object of the present invention, therefore, to provide asimple and economic process for preparing a storage-stable solid(pulverulent) low-hygroscopic form of sodium 3-hydroxy-3-methylbutyrate.

[0004] This object is achieved according to the invention by the processas claimed in claim 1.

[0005] It has been found that a solution of sodium3-hydroxy-3-methylbutyrate which is obtainable by hydrolyzing4,4-dimethyloxetan-2-one with aqueous sodium hydroxide, if appropriateafter concentration, by application to synthetic silica and, ifappropriate, subsequent drying, can be brought into a low-hygroscopic,free-flowing and readily handleable form.

[0006] Suitable synthetic silicas are, in particular, the commerciallyconventional precipitated silicas as are obtainable commercially, forexample, from Degussa under the name Sipernat®. Preferably, the solutionof sodium 3-hydroxy-3-methylbutyrate is brought to a concentration of atleast 50% by weight, particularly preferably from 70 to 80% by weight,by distilling off water under reduced pressure. At the last-mentionedconcentrations, the solution is expediently kept at a temperature of60-65° C. to prevent crystallization. The concentration can be performedon a laboratory scale, for example in a conventional distillationapparatus, or on an industrial scale, for example in a thin-filmevaporator. However, it is also possible to use directly the solutionsoccurring in the synthesis having contents of, for example, from 20 to30% by weight.

[0007] Application of the solution of sodium 3-hydroxy-3-methylbutyratecan be performed in a conventional mixing apparatus, preferably for thisa gentle mixer type is used, for example a drum mixer, plowshare mixeror cone mixer, a spray mixer or a (slow) intensive mixer. Too vigorous amixing process can, surprisingly, lead to lump formation.

[0008] Preferably, the application is performed in such a manner thatthe synthetic silica is introduced first and the solution of sodium3-hydroxy-3-methylbutyrate is added.

[0009] To decrease the water content in the finished product, thefinished product can be dried in a manner known per se. However, evenwithout drying, even at water contents of up to 30% by weight, productswhich are still free-flowing and outwardly dry are obtained.

[0010] For further improvement of the flowability, if appropriate,hydrophobic silicas (for example Sipernat® D17) or another flow improvercan be added to the product prepared according to the invention. In thiscase, for example, amounts of from 0.2 to 0.4% by weight, based on thedry matter, of hydrophobic silica can be added towards the end of themixing process and can be mixed in for a short time (for example 30min).

[0011] The solid compositions obtainable by the inventive process, whichcompositions contain sodium 3-hydroxy-3-methylbutyrate and syntheticsilica, are likewise subject-matter of the invention.

[0012] Preferably, the inventive compositions comprise at least 25% byweight of sodium 3-hydroxy-3-methylbutyrate, particularly preferablyfrom 25 to 50% by weight, based on the dry matter.

[0013] The following examples illustrate the procedure of the inventionwithout a restriction to be seen therein.

EXAMPLE 1 Preparation of a Solution of sodium 3-hydroxy-3-methylbutyrate

[0014] A solution of sodium hydroxide (127.3 g; 3.15 mol) in water (1.5l) was cooled to 0° C. Then, crude 4,4-dimethyloxetan-2-one(=β-isovalerolactone; 336.7 g; 3 mol; obtained by reacting ketene withacetone) was added dropwise in the course of approximately 2¼ h withvigorous stirring, with the temperature being kept from 1.5 to 2° C. Thereaction mixture was stirred for a further 15 min at 0° C. and thenheated for a further 40 min at 22° C. Then 415 g of water were distilledoff at 300 mbar in the course of approximately 3 h. In this manner 1533g of a solution containing approximately 27.5% by weight of sodium3-hydroxy-3-methylbutyrate were obtained.

EXAMPLE 2 Preparation of the Solid Formulation

[0015] The solution of Example 1 was concentrated to 57.5% by weight at50 mbar and 56° C. 50 g of synthetic silica (Sipernat® 50, Degussa AG)were charged in an Eirich intensive mixer (type R02). The disk rotationwas set to stage 2 (the rotating blade head was out of operation) and100 g of the solution were added in the course of 1 h via a tube. Themixing operation was then continued for a further ½ h. A homogeneouslump-free free-flowing and outwardly dry product was obtained.

1. A process for preparing solid formulations of sodium3-hydroxy-3-methylbutyrate of the formula

characterized in that, in a first process step, 4,4-dimethyloxetan-2-oneis reacted with aqueous sodium hydroxide to form a solution of sodium3-hydroxy-3-methylbutyrate, this solution, if appropriate afterconcentration, is applied, in a further process step, to syntheticsilica, and the resultant product is, if appropriate, dried.
 2. Theprocess as claimed in claim 1, characterized in that the solution ofsodium 3-hydroxy-3-methylbutyrate is concentrated under reduced pressureto a concentration of at least 50% by weight.
 3. The process as claimedin claim 1 or 2, characterized in that the application to syntheticsilica is performed in a drum mixer, plowshare mixer or cone mixer, oran intensive mixer.
 4. The process as claimed in one of claims 1 to 3,characterized in that the application to the synthetic silica is carriedout by first introducing the synthetic silica and then adding thesolution of sodium 3-hydroxy-3-methylbutyrate.
 5. The process as claimedin one of claims 1 to 4, characterized in that, to improve theflowability, hydrophobic silica is further added.
 6. A solid compositioncomprising sodium 3-hydroxy-3-methylbutyrate and synthetic silica,obtainable by the process according to claims 1 to
 5. 7. The solidcomposition as claimed in claim 6, characterized in that the content ofsodium 3-hydroxy-3-methylbutyrate, based on the dry matter, is at least25% by weight, preferably from 25 to 50% by weight.